Translation is the process where the sequence of an mRNA directs the synthesis of a specific protein. The translation of most cellular mRNA, and especially those that contain highly structured 5′-UTRs or an IRES element, depends on the formation of a functional eIF4F (eukaryotic initiation factor 4F) complex consisting of eIF4A, eIF4E and eIF4G. A. Marintchev et al., Cell, 2009; 136, 447-460. These eIF4 proteins are involved in the initiation phase of translation and help catalyze the recruitment of mRNA to the 40S ribosomal subunit to form the 48S initiation complex. eIF4F recognizes the cap structure at the 5′-end of mRNA through eIF4E, unwinds the secondary structure of the 5′-UTR region through the helicase activity of eIF4A, and binds the 43S complex through interactions between eIF4G and eIF3. A. Parsyan et al., Nature Reviews, Molecular Cell Biology, 2011; 12, 235-245.
The translation initiation factor eIF4A is a member of the “DEAD box” family of ATP-dependent helicases that acts as an RNA dependent ATPase and ATP-dependent RNA helicase to facilitate mRNA binding to the ribosome as part of the eIF4F complex. eIF4A consists of two distinct domains connected through a short linker that are both required for function. The enzymatic activity of eIF4A is stimulated by formation of a stable complex with eIF4G. The helicase activity of eIF4A either alone or as part of the eIF4F complex is increased through a transient interaction with eIF4B. eIF4A exists as a free form (eIF4Af) and as a subunit of eIF4F (eIF4Ac) and is thought to cycle through the eIF4F complex during initiation. When bound in the eIF4F complex, eIF4Ac is ˜20-fold more efficient as an RNA helicase than when found alone, leading to the proposal that eIF4Ac is the functional helicase for translation initiation. The helicase activity of eIF4F (via eIF4Ac) is thought to unwind local secondary structure in the 5′UTR of mRNAs to facilitate cap-dependent ribosome recruitment. See, e.g., U. Harms et al., Nucleic Acids Research, 2014; 1-12; A. Andreou et al., RNA Biology, 2013; 10, 19-32.
There are three eIF4A family members: eIF4AI, eIF4AII, and eIF4AIII. eIF4AI and eIF4AII show 90-95% similarity at the amino acid level, are involved in translation and are essential for growth and development. In addition to its role in translation initiation, isoform eIF4AII also has been implicated in microRNA mediated mRNA silencing. eIF4AIII is 65% similar to the other two isoforms and is involved in nonsense-mediated decay. All three eIF4A isoforms are members of the DEAD-box putative RNA helicase protein family that are characterized by seven highly conserved amino acid sequence motifs implicated in RNA remodeling. These proteins are involved in virtually all aspects of cellular RNA metabolism, including ribosome biogenesis, splicing, translation, and mRNA degradation.
eIF4A selectively regulates the translation of a subset of mRNAs. This selectivity is a result of structural elements and sequence recognition motifs found within the 5′-UTR of the mRNA. Translation inhibition can also be regulated by the tumor suppressor programmed cell death 4 (PDCD4). PDCD4 is a negative regulator of translation that binds and sequesters eIF4A. The association of PDCD4 with eIF4A induces a conformational change that prevents eIF4G from binding with eIF4A inhibiting translation initiation. C. Suzuki et al., PNAS, 2008; 105, 3274-3279.
Regulation of translation is an increasingly important field as it has implications in a range of diseases. Translation initiation is rate limiting and is dependent on the eukaryotic initiation factors. Alterations in the expression of eIF4A or factors (i.e. eIF4E, eIF4B and PDCD4) that alter its activity have been observed in many cancers. eIF4E is a well-established oncogene that regulates the translation of oncogenic mRNAs with long or structured 5′-UTRs. Overexpression of eIF4A, eIF4E and eIF4B has been associated with poor prognosis in disease indications including lymphoma, lung, colon, liver, ovarian and breast cancer. Decreased expression of PDCD4 has been linked to the development and progression of several types of cancer including lung, colon and liver. High levels of PDCD4 have been associated with good outcomes in certain types of breast cancer. See M. Bhat, Nature Reviews Drug Discovery, 2014; 14 261-278; A Modelska et al., Cell Death and Disease, 2015; 6, e1603.
Accordingly, while advances have been made in this field there remains a significant need in the art for compounds that specifically inhibit eFI4A activity, particularly with regard to eIF4A's role in regulation of cancer pathways, as well as for associated composition and methods. The present invention fulfills this need and provides further related advantages.